tbuckley/cabot-search huggingface dataset:
P15.15.B DIFFUSE ADULT-TYPE GLIOMA INFILTRATION DEFINED ON FET-PET
Authors: M Harat, I Miechowicz, J Rakowska, I Zarębska, B Małkowski
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET is a valuable tool in glioma imaging used to the definition of biopsy site, monitoring of treatment response and differentiation of treatment-related changes from glioma progression The physiological uptake within reactive astrogliosis may limits FET-PET ability to precisely define glioma extent. For the implementation of FET-PET into clinical trials, a methodological PET standardization is urgently needed to enable more precise and reproducible FET PET quantification. The primary aim of our study was to define a glioma infiltration using threshold based method between astrogliosis and tumoral tissue in FET-PET. RESULTS Astrogliosis presented similar uptake to grade 2 glioma samples. Standard threshold method (1,6x uptake in contralateral brain) in PET aquisiton 40-60 minutes post injection is effective but the accuracy decrease outside contrast enhancement within FLAIR to 56% sensitivity and 41% specificity. Adding second aquisition increased sensitivity within FLAIR to 71%. Finally, using tumor-to-plexus ratio, it is possible to differentiate astrogliosis and grade 2, and achieve sensitivity of 73% and specificty of 84% within FLAIR or 90% sensitivity with 61% specificity. ROC curves are significantly different related to method used with best results specific to new strategy. CONCLUSION Determining glioma extent using standard threshold method in PET or FLAIR is limited. Improving is possible with dual aquisition and/or different tumor to background ratio. This may largely improve delineation of glioma for surgery or radiotherapy.
P12.13.B FIBROBLAST ACTIVATION PROTEIN AS A POTENTIAL THERANOSTIC TARGET IN BRAIN METASTASES OF DIVERSE SOLID TUMOURS
Authors: B Vymolova, M Zubal, I Matrasova, P Vymola, J Veprkova, M Syrucek, R Tomas, Z Vanickova, E Krepela, D Konecna, P Busek, A Sedo
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Brain metastases (BM) are a common complication of oncologic disease associated with dismal prognosis and there is an urgent need for novel therapeutic approaches. Fibroblast activation protein (FAP), a transmembrane serine protease, is an emerging theranostic target in cancer due to its frequent upregulation in the tumour microenvironment. FAP protein itself and/or FAP+ cells were shown to promote cancer progression in several extracranial malignancies. However, very little is known about the expression of FAP and the role of FAP+ cells in the unique microenvironment of BM. In this study, we quantified FAP expression and characterized FAP+ cells in BM of various origin. MATERIAL AND METHODS FAP enzymatic activity and protein concentration were determined in samples of BM (n=58) and control non-tumorous brain tissue (n=12) by an enzymatic assay using a specific fluorogenic substrate, western blot, and ELISA. Expression of FAP and the characteristics of FAP+ cells were analysed by IHC (n=112). Expression of collagen was quantified by Masson´s trichrome staining (n=106) and collagen I concentration was measured by ELISA (n=56). RESULTS FAP expression was significantly higher in BM in comparison to non-tumorous brain tissue, both at the protein and enzymatic activity level. BM with higher FAP expression displayed higher levels of collagen I. FAP was predominantly confined to stromal cells expressing markers typical of cancer-associated fibroblasts and residing in collagen rich regions. FAP expression on tumour cells in a portion of BM was also noted , mainly in BM originating from lung, breast, and renal cancer, melanoma, and sarcoma. Increased FAP expression and the presence of FAP+ stromal cells were common features of BM irrespective of their origin. CONCLUSION We are the first to provide a detailed analysis of FAP expression in BM of diverse origin and characterise FAP+ cells in their microenvironment. The frequent upregulation of FAP and its presence on both stromal and tumour cells support the use of FAP as a promising theranostic target in BM. Funding: This research was funded by the Charles University grant no. 342522 and Program Cooperatio, research area ,,Oncology and Haematology"; Ministry of Health of the Czech Republic - grant NU22-03-00318; Ministry of Education, Youth and Sports of the Czech Republic - LM2023053 of EATRIS-CZ and project “Center of Tumor Ecology” (CZ.02.1.01/0.0/0.0/16_019/0000785) - Operational Program Research, Development and Education; project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) by the European Union - Next Generation EU.
P18.10.B WHICH MENINGIOMAS BENEFIT MOST FROM METHYLATION PROFILING?
Authors: F Ruiz, L D'Antona, M Dutt, P Mariathasan, A Merve, Z Jaunmuktane, F Sahm, S Brandner
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND methylation profiling combined with copy number assay provide a better prognostication than WHO grade alone. Profiling all meningiomas is financially unsustainable in most centres, therefore pathologists and clinicians ask for guidance which meningiomas to analyse. Here, we analysed how the WHO grades resolve into methylation classes and risk strata, to provide guidance on which meningiomas to profile MATERIAL AND METHODS From 2018-2023 a subset of meningiomas diagnosed within our institution, and all referred meningiomas underwent methylation profiling with copy number assay. Using the classifier 12.6 we determined how the 3 CNS WHO grades (in short G1, G2, G3), resolve into the methylation classes (MC) benign, intermediate, or malignant, or the risk strata low, intermediate, and high [PMID 36377252, 34618539] RESULTS Of 1408 locally diagnosed meningiomas, 309 (22%) underwent profiling and 393 meningiomas were referred. Of these 702 meningiomas, 545 had a calibrated score of &amp;gt;0.90. Of 253 G1 meningiomas 231 (91%) allocated to MC benign, and 22 (9%) into MC intermediate. Instead, of the 214 G2 meningiomas, 124 (58%) allocated to MC benign, 77 (36%) to MC intermediate and 13 (6%) into MC malignant. The 17 G3 meningiomas distributed approximately equally into the 3 MC’s. Similarly, when analysing the allocation to integrated risk scores, of the 214 G2 meningiomas, 71 (33 %) were low, 106 (50%) intermediate, and 37 (17 %) high risk. None of the 16 G3 meningiomas had a low risk score, whilst 5 had an intermediate, and 11 a high risk score. When stratifying G2 meningiomas by grading criterium (brain invasion, mitotic count, histological type) there was a similar risk score distribution across the 3 criteria. CONCLUSION G2 meningiomas show the most notable discrepancy between grade and methylation class or risk score, and thus should preferentially undergo methylation profiling. Instead, most G1 meningiomas have a low, and most G3 meningiomas a high risk score.
OS10.7.A TUMOR-ASSOCIATED ASTROCYTES PROMOTE TUMOR PROGRESSION OF SONIC HEDGEHOG MEDULLOBLASTOMA BY SECRETING LCN2
Authors: Q Chang, H Li
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor-associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive. MATERIAL AND METHODS We explored the function of TAAs of SHH-MB in transgenic mouse model and co-culture system by a series of molecular biological techniques. To illuminate the TAAs distribution pattern during tumor progression of MB, we firstly detected MB transgenic mice bearing tumor at different time points by nuclear Magnetic resonance imaging (MRI). Histologic sections were then evaluated under microscope after H&amp;E staining. The RNA-sequencing was also performed to evaluate differential expression between normal astrocytes (ASs) and tumor-associated astrocytes (TAAs). Bio-informatic analysis was followed to find the specific gene expressed in TAAs. Drug treatment of TAA inhibitor was finally applied in the animal model to clarify its effects on tumor progression. RESULTS We illuminated that TAAs showed a specific and dynamic pattern during SHH-MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early-stage tumors and dissemination foci. We further demonstrated that LCN2 secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. CONCLUSION We for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs.
P06.09.B TRIAL IN PROGRESS: PHASE 1 DOSE-FINDING STUDY TO EVALUATE SAFETY AND TOLERABILITY OF CVGBM IN PATIENTS WITH NEWLY DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: G Tabatabai, L von Baumgarten, M van den Bent, M C Burger, P Freres, M Glas, P Hau, U Herrlinger, I Mildenberger, B Neyns, H Schäfer, C Seidel, F de Vos, R Galot, N Whenham, A Wick, M Falk, L de Freitas Chama, J Henze, P Kelemen, S D Koch, J Lutz, R Heidenreich, P Romer Roche, T Rost, O Schönborn-Kellenberger, U Gnad-Vogt
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is characterized by a low mutational burden limiting the number of neoantigen targets for cancer vaccines. Vaccination against tumor-associated antigens over-presented via MHC class I and II in GBM is an alternative that has shown promise in previous trials. One cancer vaccine containing peptides presented by HLA-A*02-01 (class I) and some DR alleles (class II), showed evidence of peripheral vaccine-induced immune response against these peptides in patients with GBM. Our study will assess the safety and immunogenicity of the messenger ribonucleic acid (mRNA)-based multiepitope vaccine CV-GBM, an investigational therapeutic mRNA vaccine, encoding eight of these peptides that have demonstrated immunogenicity as peptide vaccines. CV-GBM consists of a mRNA with unmodified nucleotides formulated with lipid nanoparticles. MATERIAL AND METHODS CV-GBLM-001 is a first-in-human, open-label, international, dose-escalation phase 1 trial. HLA-A*02:01-positive patients with newly diagnosed MGMT-unmethylated GBM (CNS WHO Grade 4), including IDH-wildtype astrocytoma with a molecular signature of unmethylated MGMT-GBM who have had a gross total or partial resection and who completed post-surgery radiotherapy with or without chemotherapy, are eligible to receive CVGBM. The trial comprises a dose-escalation part (Part A) followed by a dose-expansion part (Part B). In Part A, the starting dose is 12 µg mRNA, which may be escalated to 25 µg, 50 µg and 100 µg, with 3 to 6 patients per dose level. Dose escalation will be guided by a Bayesian logistic regression model. Patients will receive 7 doses of CVGBM by intramuscular injection on Days 1, 8, 15, 29, 43, 57, and 71, followed by 6 optional doses at 6-week intervals, up to 1 year after the first dose or until disease progression or intolerable toxicity. An independent Data and Safety Monitoring Board will recommend the dose for expansion in Part B in which about 20 patients will be enrolled. Biomarkers and vaccine-induced innate and adaptive immunogenicity, including, but not limited to, systemically induced cytokines and chemokines and antigen-specific CD4+ and CD8+ T cells, will be monitored in the blood, and optionally in vaccine-draining lymph nodes and relapsed tumor. In addition to the primary safety objectives, secondary objectives of efficacy (progression-free survival, overall survival) and patient-reported quality of life outcomes will be assessed. Trial sponsor: CureVac SE, Germany.
P04.06.A A PHASE II MONOCENTRIC STUDY OF LIMITED USE OF HIGH DOSE OF CHEMOTHERAPY AND PROTON THERAPY IN PEDIATRIC HIGH RISK MEDULLOBLASTOMA AND OTHER EMBRYONAL CANCERS
Authors: M Guidi, C Fonte, M Tellini, B Castelli, C G Gori, L Giunti, M Di Nicola, A M Buccoliero, C Caporalini, F Giordano, B Rombi, I Desideri, A Pugi, K Tortora, D Greto, L Genitori, M Leo, I Sardi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Despite the multimodal approach, medulloblastoma remains a leading cause of cancer-related death in children. We proposed the preliminary data of an interventional, open-label, phase II study to evaluate the safety and efficacy of standard and high-dose chemotherapy associated with craniospinal proton therapy in patients with metastatic medulloblastoma and other embryonal cancers. MATERIAL AND METHODS A total of 19 patients have been enrolled from the beginning of the study from February 2018 to May 2022 . The median age was 7,5 years (range; 13 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, pineoblastoma or other high risk embryonic tumors were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months. RESULTS At December 2022, the median follow up was 23 months. 18 patients had high risk medulloblastoma and one had a primary leptomeningeal primitive neuroectodermal tumor. After the induction phase 14 patients showed CR, 3 PR, 1PD, 1SD. At subsequent re-evaluations two of the three patients with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. At the end of proton therapy 18 patients had CR. During the reporting period three patient died for progression of the underlying disease. At 15 months from the start of treatment the PFS and OS were 68.8% (95% CI: 34.1% - 87.6%) and 94.7% (95% CI: 68.1% - 99.2%) respectively. The principal expected side effects of chemotherapy were hematology toxicity (fever and neutropenia prevalent after etoposide and carboplatin plus vinorelbine). Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation. CONCLUSION As the study did not reveal any safety issues, proton therapy combined with intensive chemotherapy, and myeloablative chemotherapy only in selected cases and always before irradiation, proved feasible and successful in treating high-risk medulloblastomas and other embryonal tumors.
P01.05.A COGNITIVE OUTCOMES IN ADULT MENINGIOMA PATIENTS AFTER SURGERY WITH OR WITHOUT RADIOTHERAPY
Authors: L De Roeck, L Coolkens, S De Vleeschouwer, C Sleurs, M Lambrecht
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Meningioma patients often report cognitive complaints after therapy, profoundly impacting health-related quality of life. However, prevalence of these cognitive sequelae is inconsistent across trials. Moreover, meningioma patients often suffer from severe anxiety after treatment compared to healthy controls, possibly adversely affecting cognition. MATERIAL AND METHODS In this cohort study, 41 adult WHO grade 1 and 2 meningioma patients underwent comprehensive cognitive testing, covering the domains of memory, executive functioning, visuomotor functioning, attention, and language. Cognitive scores were transformed into z-scores using normative data adjusted for age, education, and sex. Patients were categorized as cognitively impaired if at least 2 tests scores differed ≥ - 1.5 SD or if at least 1 test score differed ≥ - 2.0 SD from the reference mean. Moreover, all patients filled out an online self-report inventory, assessing anxiety. Anxiety, age at diagnosis and treatment modality were included as predictors in a linear regression model per cognitive domain. Bonferroni correction was applied to correct for multiple testing. RESULTS In this cohort, 26 out of 41 patients showed cognitive impairment (63,4%) and the same number reported to have higher anxiety levels compared to the norm. Patients performed worse than the norm in cognitive domains of language and visuomotor functioning. No significant differences were found in cognitive outcomes regarding therapy, being either surgery (n=31) or surgery followed by cranial radiotherapy (n=10). Age at time of diagnosis was the only significant predictor of language (p=.005) and attention (p=.015) performance, with worse performance in case of diagnosis at younger age. No impact of anxiety nor treatment modality was found in this study. CONCLUSION More than half of meningioma patients showed to be cognitively impaired after surgery with or without radiotherapy treatment, mostly in domains of language and visuomotor functioning. Younger patients could be affected more by language and attention difficulties in their daily lives. Given their more active stage in life, this can have an important impact. This effect was independent of emotional functioning. These findings will need to be validated in larger prospective longitudinal trials.
P10.18.B JUGLONE AS A NOVEL EPIGENETIC DRUG FOR GLIOBLASTOMA
Authors: A Barciszewska, A Belter, I Gawrońska, M Giel-Pietraszuk, M Z Naskręt-Barciszewska
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor and one of the human malignancies with the highest mortality. Standard approaches for GBM, including, gross total resection, radiotherapy, and chemotherapy, cannot destroy all the cancer cells and, despite advances in its treatment, the prognosis for GBM remains poor. The, until now, the most successful chemotherapy with temozolomide (TMZ) for brain gliomas is not fully effective, and therefore new therapeutic strategies for GBM are needed. We found that juglone (J), which exhibits cytotoxic, anti-proliferative, and anti-invasive effects on various cells could be a promising agent for GBM therapy. MATERIAL AND METHODS We analyzed the effects of juglone alone and in combination with temozolomide on glioblastoma cell lines. In addition to the analysis of cell viability and cell cycle, we looked at the epigenetic effects of these compounds on cancer cells. We estimated the total DNA methylation in T98G, U138, U118, and HaCaT lines after treatment with different J and J/TMZ concentrations and incubation time using TLC separation of radioactively labeled nucleotides. The combination treatment with J and TMZ was evaluated with total DNA methylation analysis and 8-oxo-dG (oxidative stress marker) estimation using EC detection. RESULTS We noticed concentration and time-dependent changes in total DNA methylation. The highest increase was observed for the T98G cell line at the incubation time of 24hrs. Normal cell line (HaCaT) did not present significant changes. TMZ alone induced a lowering of DNA methylation, but juglone diminished that effect. J induces minute oxidative stress in low concentrations, but is quite high and rapid at concentrations over 50uM, concomitantly with none/slight decrease in DNA methylation. However, the combination of J/TMZ in increasing concentrations diminished the oxidative stress effect. CONCLUSION Our results strongly suggest that a combination of juglone and temozolomide can be applied for better GBM treatment. At certain incubation times and concentrations, juglone increases DNA methylation, which is a positive therapeutic effect in oncogenesis. Small doses of J keep a low level of 8-oxo-dG with an increase in DNA methylation. The combination of J/TMZ in high concentrations of both drugs decreases the oxidative stress effect of chemotherapy. The study was supported by OPUS 19 (2020/37/B/NZ5/03249) grant from the National Science Center, Poland.
P09.04.B PNES IN BRAIN TUMOR PATIENTS : AN UNEXPECTED CHALLENGE
Authors: R Loebenstein, M Eltity, E Magiel, O Haisraely, A Noga, E Jan, M Boxer, A Taliansky
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Epileptic seizures (ES) are common in brain tumor patients. The phenomenon of psychogenic non-epileptic seizures (PNES) amongst those patients has not been well described. PNES Phenomenology could be similar to ES, however, epileptogenic activity on electro-encephalogram (EEG) is absent. The diagnosis of PNES can be challenging in brain tumor patients since both types of seizures can present with similar symptoms and might occur together. Risk factors for the development of PNES include a history of negative events in childhood, exposure to trauma, history of psychiatric illness and chronic pain, and substance abuse. Diagnosing PNES is important for delivering the appropriate treatment, and preventing the toxic influence of unneeded treatment and procedures. MATERIAL AND METHODS The Electronic files of patients with ES and PNES were evaluated, in A retrospective analysis from the database of the Neuro-Oncology unit at Sheba Medical-Center. RESULTS 4 patients with brain tumor related epilepsy and PNES were identified: a female 22 years old with right frontal IDH1 mutated non 1p/19q deleted glioma WHO2, a 44 years old male with right frontal IDH1 mutated 1p/19q deleted glioma WHO2, a 48 years old female with left temporo-insular IDH1 mutated non 1p/19q deleted glioma WHO2 and a 65 years old female with multiple radiation induced meningiomas. Seizures semiology were compatible with the lesions. The first two patients had recent stress factors, and the last two suffered severe diagnosis-related anxiety. All patients presented initially with ES and developed PNES subsequently. They were treated with 2-4 Anti-Epileptic drugs(AED’s). They were referred to EEG video monitoring due to worsening seizures frequency despite increasing the AED’s and no evidence of tumor progression at that time. All patients had clinical seizures which did not have any epileptiform activity correlation on Video-EEG. Hence, PNES was diagnosed. Three patients underwent psychological treatment and two patients received medical therapy for underlying psychological factors contributing to PNES. Seizure frequency and number of AED's decreased in all patients. CONCLUSION In patients with brain tumors the diagnosis of PNES can be challenging but should be considered in patients with increased seizures frequency regardless of stable imaging and absence of any other provocative factors. Video EEG is pivotal for PNES diagnosis. Psychological consulting and treatment are recommended in PNES cases. Correct diagnosis and treatment will contribute to the patient's quality of life.